Amyloidosis refers to the pathological deposition of proteins in the form of congophilic, green birefringent fibrils, when congo red-stained, either dispersed or in the form of localized amyloidomas. Such deposits are symptomatic of several diseases, for example Alzheimer's Disease, inflammation-associated amyloid, type II diabetes, bovine spongiform encephalopathy (BSE), Creutzfeld-Jakob disease (CJD), scrapie and primary amyloidosis.
Amyloidoses are generally categorized into three groups: major systemic amyloidoses, major localized amyloidoses, and miscellaneous amyloidoses. Major systemic amyloidoses include: chronic inflammatory conditions (e.g., tuberculosis, osteomyelitis, etc.); non-infectious conditions such as juvenile rheumatoid arthritis, ankylosing spondylitis and Crohn's disease, etc.; familial Mediterranean Fever, plasma cell dyscrasia (primary amyloidosis) and various familial polyneuropathies and cardiomyopathies. Major localized amyloidoses include: chronic dialysis usually for greater than 8 years, Alzheimer's disease, Down syndrome, Hereditary cerebral hemorrhage (Dutch), and non-traumatic cerebral hemorrhage of the elderly. Miscellaneous amyloidoses include: familial polyneuropathy (Iowa), familial amyloidosis (Finnish), hereditary cerebral hemorrhage (Icelandic), CJD, Medullary carcinoma of the thyroid, atrial amyloid, and diabetes mellitus (insulinomas). Other amyloidoses include those referenced in Louis W. Heck, “The Amyloid Diseases” in Cecil's Textbook of Medicine 1504-6 (W.B. Saunders & Co., Philadelphia, Pa.; 1996).
Transmissible spongiform encephalopathies which cause CJD and Gerstmann-Strässler-Scheinker (GSS) disease are described by B. Chesebro et al., “Transmissible Spongiform Encephalopathies: A Brief Introduction” in FIELD'S VIROLOGY 2845-49 (3rd Edition; Raven Publishers, Philadelphia, Pa.; 1996) and in D. C. Gajdusek, “Infectious amyloids: Subacute Spongiform Encephalopathies as Transmissible Cerebral Amyloidoses,” 2851-2900 in FIELDS VIROLOGY (1996). Many of these diseases are likely mediated by prions, an infectious protein. See S. B. Prusineri, “Prions” in FIELDS VIROLOGY 2901-50 (1996) and the references contained therein. The inherited forms of amyloidoses as described on Online Mendelian Inheritance in Man (OMIM) “www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?” Each of the above is incorporated herein by reference.
Very rarely do patients with clinically proven amyloidosis spontaneously achieve complete remission, perhaps because the amyloid fibrils themselves are non-immunogenic. Various therapies for amyloidosis have been investigated, such as high-dose chemotherapy, steroids, iodinated doxorubicin, and stem cell replacement therapy. However, in only one type of amyloid disease, Familial-Mediterranean amyloidosis, has drug treatment (with colchicine) been shown to be effective.
The use of monoclonal antibodies (mAbs) to induce or modulate the immunological removal of an otherwise unrecognized entity is known. mAbs have been successfully used in treating non-Hodgkins lymphoma and breast cancer, for example.
Previously, a variety of studies have characterized antibodies that bind to amyloid proteins or amyloid fibrils. See, for example, U.S. Pat. Nos. 5,714,471; 5,693,478; 5,688,651; 5,652,092; 5,593,846; 5,536,640; 5,385,915; 5,348,963; 5,270,165; 5,262,332; 5,262,303; 5,164,295; and 4,782,014. In addition, several publications have suggested that anti-amyloid antibodies might be useful for studying the progression of beta-amyloidosis and for various therapeutic options. See, for example, Bellottii et al., Scand. J. Immunol. (1992) 36(4):607-615; Bellotti et al., Ren. Fail. (1993) 15(3):365-371; Walker et al. J. Neuropathol. Exp. Neurol. (1994) 53(4):377-383; and Bickel et al., Bioconjug. Chem. (1994) 5(2):119-125. However, no therapeutic antibody has been demonstrated to halt or reverse the deposition of amyloid fibrils in a patient. Thus, a need exists for a method for treating amyloidoses using antibody formulations containing antibodies that bind to amyloid fibrils.